A protocol for a systematic review of clinical practice guidelines for the antenatal management of dichorionic diamniotic twin pregnancy

Overview: The protocol outlines the process designed to systematically review clinical practice guidelines (CPGs), addressing the antenatal management of dichorionic diamniotic (DCDA) twin pregnancies. Background: CPGs are statements that include recommendations intended to optimise patient care, that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options. CPGs are typically created by scientific institutes, organisations and professional societies, and high-quality CPGs are fundamental to improve patient outcomes, standardise clinical practice and improve the quality of care. While CPGs are designed to improve the quality of care, to achieve this, the identification and appraisal of current international CPGs is required. Because twin pregnancies are identified as high-risk pregnancies, a systematic review of the CPGs in this field is a useful first step for establishing the required high level of care. Aim: The aim of the systematic review is to identify, appraise and examine published CPGs for the antenatal management of DCDA twin pregnancies, within high-income countries. Methods: We will identify published CPGs addressing any aspect of antenatal management of care in DCDA twin pregnancies, appraise the quality of the identified CPGs using the Appraisal of Guidelines for Research and Evaluation version 2 (AGREE II) the Appraisal of Guidelines Research and Evaluation – Recommendations excellence (AGREE-REX) instruments and examining the recommendations from the identified CPGs. Ultimately, this protocol aspires to clearly define the process for a reproducible systematic review of CPGs within a high-income country, addressing any aspect of antenatal management of DCDA twin pregnancies. PROSPERO registration: CRD42021248586 (24/06/2021)


Introduction
Twin pregnancies are fundamentally defined and managed according to their chorionicity (number of outer membranes in a multiple pregnancy) and amnionicity (number of inner membranes that surround babies in a multiple pregnancy) 1 .A twin pregnancy can originate from the fertilisation of two oocytes (dizygotic) or from the fertilisation of one oocyte that splits (monozygotic).Dizygotic twin pregnancies will always be dichorionic diamniotic (DCDA) and have previously been referred to as non-identical twins or fraternal twins.A monozygotic twin pregnancy, also referred to as identical twins, can be comprised of dichorionic diamniotic (30%), and monochorionic monoamniotic diamniotic or monochorionic diamniotic (70%); the chorionicity and amnionicity is determined by the time between fertilisation and embryonic cleavage 2 .Globally monozygotic twins occur in 3.5 per 1000 pregnancies, and this rate remains relatively constant 3 .Interestingly, rates of dizygotic twins vary according to geographical location, with Nigeria having the highest incidence, 40 of every 1000, and Japan the lowest at 6.7 per 1000 4 .
There is global consensus that twin pregnancies are higher risk compared to singleton pregnancies because they increase the risk of morbidity and mortality for the mother and child, and they present unique challenges for both families and health care providers 5 .Maternal obstetric morbidities are observed more commonly 6,7 and there is an increased perinatal risk of adverse outcomes including preterm birth, intrauterine growth restriction and congenital abnormalities, thus contributing to a higher incidence of perinatal mortality [8][9][10][11] ).The MMBRACE (Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK) published its report on the Confidential Enquiry into Stillbirth and Neonatal Death in Twin Pregnancies in January 2021 and reported 'major sub-optimal antenatal care in 50% of pregnancies' and 'in around 1 in 2 baby deaths, the care was poor, and that if the care had been better it may have prevented the baby from dying' 12 .
Given the associated risk with twin pregnancies and the related adverse outcomes, there is a need for consistent clinical care of twin pregnancies that follows the best evidence-based practice.To safeguard the effectiveness of clinical practice and future research we need to ensure the clinical guidelines are of high quality and gaps are identified as a focus for future guideline development and updates.
Chorionicity is one of the most important factors influencing perinatal outcome in twin pregnancies and is ideally diagnosed in early pregnancy [13][14][15] .Dichorionic twin pregnancies are most common and account for 70% of twin pregnancies, while monochorionic account for 30% 16 .Diagnosis of placental chorionicity is essential for the management of twin pregnancies, as intertwin vascular anastomoses are present in most monochorionic twin placentas, leading to unique complications 17 .In recognition of the unique complications associated with monochorionic twin pregnancies specific international guidelines exist to address the management of these pregnancies.
Clinical practice guidelines (CPGs) are "statements that include recommendations intended to optimise patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options" 18 .CPGs are typically created by scientific institutes, organisations and professional societies, and high-quality CPGs are fundamental to improve patient outcomes, standardise clinical practice and improve the quality of care 19,20 .CPGs for the management of twin pregnancies exist at national and international level, however the amount, quality and consistency of these CPGs is currently unknown.

Aim of this review
The aim of this systematic review is to identify, appraise (using the Appraisal of Guidelines for Research and Evaluation version 2 (AGREE II) and the Appraisal of Guidelines Research and Evaluation -Recommendations excellence (AGREE REX) tools) and examine published clinical practice guidelines (CPGs) for the antenatal management of dichorionic and diamniotic (DCDA) twin pregnancies, within high income countries.
The specific objectives are to:

Protocol
The present protocol has been registered (24/06/2021) in the International Prospective Register of Systematic Reviews database (PROSPERO ID: CRD42021248586) and is reported in accordance with the reporting guidance provided in the Preferred Reporting Items for Systematic review and Meta-Analysis -Protocols (PRISMA-P) 2015 21 ; the completed checklist is available in Reporting guidelines 22 .The study is based at Cork University Maternity Hospital, Ireland between 2021 and 2022 and will focus on an international review of clinical practice guidelines.In recognition of the tailored approach that a systematic review of clinical practice guidelines requires, and in recognition of the need for a systematic and reproducible method, a methodological guide for conducting systematic reviews of CPGs was followed during the design of this protocol 23,24 .

Eligibility criteria
The eligibility of CPGs included will be based on the inclusion and exclusion criteria applied to the PICAR framework 24 , (P: population, clinical indication(s) and condition(s), I: intervention(s), C: comparator(s), comparison(s) and (key) content, A: attributes of eligible CPGs and R: recommendation characteristics) (Table 1).The search will not contain language restriction and the CPGs will be sought from 2000 to 2021.This systematic review will exclude any recommendations specific to monochorionic pregnancies.For the purpose of this Table 1.PICAR framework (DCDA, dichorionic and diamniotic).

Study population
• All guidelines referring to antenatal management of DCDA twin pregnancy, in high income countries.

Clinical Investigation
• Antenatal management of DCDA twin pregnancies

Clinical condition
• DCDA twin pregnancy is defined as each fetus having their own separate placenta with its own separate inner membrane (amnion) and outer membrane (chorion).For the purpose of this review, there is a specific focus on antenatal management of DCDA twin pregnancies.
• The antenatal period extends from the start of pregnancy to the onset of labour and antenatal care is "essential for protecting the health of women and their unborn children.

Interventions
• Any intervention focusing on the antenatal management of DCDA twin pregnancies

Comparator(s), Comparisons, and (key) Content
• Any comparator or comparison • Key clinical practice guideline (CPG) content of interest is DCDA twin pregnancy antenatal management

Attributes of eligible CPGs Scope
• Cover any aspect of antenatal care for DCDA twin pregnancies.
• Must be published

Language
• Full text CPGs in any language

Year of publication • 2000 onwards
Developing/ publishing organisation • CPGs issued or endorsed by national or international scientific societies, professional colleges, charitable organisations, and government organisations will be included.
• State/province guidelines will be included e.g.Australia and Canada, where states work independently.

Country of publication
• High income countries (83 countries), as defined by the world bank 25 .This is due to the large discrepancies in care systems and management of care between high, low and middle-income countries 26 .

Quality of evidence
• No maximum quality score based on the AGREE II and AGREE-REX instruments are required for eligibility.ALL relevant CPGs will be included in the review.
• The quality score will be used to interpret the review findings and will be addressed in the discussion.

Recommendations characteristics and ' other' considerations
• Eligible recommendations should be applicable to antenatal care of DCDA twin pregnancies.
• Recommendations will be considered if they are located anywhere within the guideline document (e.g.main text, algorithms or tables).• Guidelines addressing any aspect of antenatal management of DCDA twin pregnancies without recommendations are eligible for inclusion review, CPGs are defined as "systematically developed statements, to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances" 20 .

Information sources
The identification of relevant CPGs will encompass a multitiered approach.This search strategy is developed to identify CPGs concerning the antenatal management of DCDA twins, from the year 2000-2021, throughout a broad network of information sources.Systematic bibliographic database searching will identify CPGs published in journals; others will be identified through online searches of grey literature and guideline repositories, or through professional bodies/ organisations.We will search for the relevant professional bodies of all highincome European Union (EU) countries (as defined by the world bank), Scandinavian countries, and any high-income Englishspeaking country outside of the EU.If the professional bodies locate their CPGs behind paywalls, do not have CPGs on their website, or if they do not have a website, we will contact them requesting any relevant CPG(s).
A systematic literature search will be performed, covering CPGs published from 2000 to 2021, using the following databases: PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), MEDLINE, Web of Science and OpenGrey.The guideline repositories and professional bodies/organisations are identified in Table 2 and Table 3.

Search strategy
The search strategy was developed with a researcher/midwife (COC), medical librarian (SB), a senior researcher (SL) and a maternal-fetal medicine subspecialist (KOD).The search strategy will include suitable keywords relating to two clinical concepts.The terms will be followed by the truncation symbols * and will be refined using Boolean operators such as AND/OR.Table 4 represents an example of search terms; this will be tailored to each database as appropriate.The search fields will consist of a full text search, on humans only, from 2000-2021.
A full text search will be conducted to identify any recommendations specific to DCDA twin pregnancies that may be nested within other guidelines.The search strategy will be developed on a Microsoft word file and will be piloted before the final searches are executed.See Extended data 22 for a sample search strategy.

Study selection
Retrieved records from the database and website (Table 2 & Table 3) screening will be imported into Mendeley, and duplicates will be removed using the 'check for duplicates' function.They will then be imported into Rayyan 27 and screened again for duplicates using the 'detect duplicates' function.Two independent reviewers (COC and EOC) will screen the records and highlight any guideline meeting the eligibility criteria outlined in Table 1.Records not meeting the eligibility criteria will be excluded.Reviewers will cross examine approx.10% of the other reviewers' decisions and any discrepancies identified will be discussed.The PICAR framework will be applied broadly during the initial screening to ensure relevant CPG's are not excluded 24 .inclusion.The 'blind function' will be activated at this point on Rayyan and to qualify for inclusion, a CPG will receive a 'Yes' from both reviewers.Any disagreements will be resolved following discussion and consensus.If consensus on eligibility cannot be agreed, a third reviewer with clinical expertise (KOD) will be consulted for input.A PRISMA flow diagram will be created to illustrate the search process.This diagram will map out the process for CPG selection and the number of records identified at each stage based on inclusion and exclusion criteria.

Data collection
Following identification of relevant CPGs, all associated supplementary documents will be retrieved by COC prior to data extraction and quality assessment.If links to these documents are not provided within the CPG, COC will conduct a search to locate them.All supplementary documents will be verified by EOC to ensure completeness and correct document pairing.

Data extraction
Data extraction will be completed by one reviewer (COC) and will be independently verified by EOC for accuracy and completeness.A data extraction form will be designed and adapted based on the methodology applied in previous research of CPGs in the field of obstetrics (the RECURRENT study) 24 .This will be pilot tested to meet the study specified requirements and then applied for the data extraction of the current systematic review 28 General information and recommendations for all included CPGs will be extracted using the structured data extraction form in Microsoft Excel.Discrepancies will be resolved through discussion and consensus.If consensus cannot be reached a third reviewer with will be involved (KOD).Any missing information from the CPGs will be recorded as 'not described' (ND) in the data extraction form.
The following information will be extracted from the included CPGs: Clinical guideline

Quality assessment and risk of bias
The quality of the included CPGs will be assessed using the AGREE II and AGREE-REX tools 29,30 .
The AGREE II tool is used to assess the CPG development process as a whole 31 .The criteria encompass 23 items, over six domains and is rated on a 7-point Likert scale.The domains include (i) Scope and purpose (ii) Stakeholder involvement in the development of the guidelines (iii) Rigour of development (iv) Clarity of presentation (v) Applicability (vi) editorial independence in the formulation of recommendations.A noted limitation the AGREE II tool is that scores do not correlate to the quality of the recommendations within the CPG 32,33 .
The AGREE-REX tool was designed as a compliment to AGREE II in response to its noted limitations and focuses specifically on the recommendations within the CPG 31 .AGREE-REX evaluates clinical credibility (are the recommendations evidence based) and ease of guideline implementation.The AGREE-REX instrument will be applied to a group of recommendations within the guidelines rather than the guideline as a whole, as this study will look at the antenatal management of DCDA twin pregnancy (only selected recommendations are of interest).The criteria encompass nine items, over three domains and is rated on a 7-point Likert scale 29 .The domains include (i) clinical applicability (ii) values and preferences, (iii) implementability.
Two reviewers (COC and EOC) will conduct the quality assessment of the CPGs.The process will be guided by a researcher with methodological experience (SL).Independent appraiser scores will be used to calculate domain scores for AGREE II.AGREE-REX scores will be calculated through consensus of both reviewers, AGREE-REX requires either a consensus score or 5 independent appraisers as per instructions.If consensus cannot be research, a third reviewer (KOD) will assist.The score for each assessment tool will be calculated for each domain independently and we will scale the total as a percentage of the maximum possible score for that domain (as per instructions).To enable fair comparison of the scores, our review will report overall outcomes categorically, using a 5-point Likert scale adapted by previous peer-reviewed systematic reviews 28,32,34 : excellent (81%-100%), good (61%-80%), average (41%-60%), fair (21%-40%) and poor (0%-20%).

Data synthesis
As this will be a narrative systematic review, data synthesis and reporting of results will involve a descriptive approach.We will describe the quality appraisal using the AGREE tools scoring, critically reflect on the content within the CPGs, examine any potential shortcomings and establish international comparisons between both the CPG and their recommendations.Recommendations will be assigned to categories; each category title will be decided following review of all recommendations within the CPGs.

Study status
We are currently conducting full text screening for this systematic review.The study protocol, database/ organisation/ guideline repository search and the preliminary screening are completed.

Conclusion
The aim of this systematic review is to identify, appraise and examine published CPGs, in high income countries for the management of antenatal care in DCDA twin pregnancies.All twin pregnancies are considered high risk because of the associated increased risk of maternal and neonatal morbidity and mortality.Intertwin vascular anastomoses are present in most monochorionic twin placentas, necessitating different medical management to DCDA twin pregnancies.In recognition of the different care pathways associated with chorionicity, this study will focus on the antenatal management of DCDA twins only.Guidelines are needed to improve the quality of care and standardise clinical practice 35 .Because twin pregnancies are identified as high-risk pregnancies, with a need for consistent clinical care, a systematic review of the CPGs in this field is a useful first step as a prerequisite for establishing the required high level of care.

Nomenclature:
It is recommended to use the conventional nomenclature "dichorionic diamniotic" instead of "dichorionic and diamniotic" for clarity and consistency.

Table 4: Search Strategy
Although the supplied search strategy is an example, it would be beneficial to include abbreviations such as "DCDA" and terms like "DC twin*" which are commonly used in the literature.
Overall, this protocol presents a robust framework for conducting a systematic review on this important topic.Addressing the above points will further strengthen the protocol and ensure its comprehensive nature.
Is the rationale for, and objectives of, the study clearly described?Yes

Are sufficient details of the methods provided to allow replication by others? Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: I specialize in clinical work within obstetrics and fetal medicine, with a primary research focus and PhD on multifetal pregnancies, particularly twin pregnancies.I have contributed to the development and revision of multiple national guidelines within the fields of obstetrics and fetal medicine.My expertise includes conducting systematic reviews, as well as performing advanced literature searches and evaluations.
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
Yasser Amer The authors have selected a high risk and priority condition, antenatal management of dichorionic diamniotic twin pregnancy, to conduct a systematic review (SR) of published guidelines using the golden standard for quality assessment of guidelines: the AGREE II Instrument in addition to its new complementary tool: AGREE-REX.They registered their protocol in PROSPERO as well.
The aim of the study and its methodology section are both well-written, clear, and detailed.
Systematic reviews and quality appraisals of clinical guidelines are among the invaluable resources that can inform the decision-making of clinicians in general and for obstetricians in particular in this article.
Using highly cited and validated tools like AGREE II and AGREE-REX is an added value to this work (as recommended by the EQUATOR Network).Moreover, the results may inform guideline development or adaptation for the same health topic that is one of the care gaps in MCH.
I would recommend adding a statistical analysis in the form of an inter-rater analysis (K statistics) and graphical representation of the 23-items scores (1-7 Likert scale) and the 6 domain scores in addition to the 2 overall assessments (%) of AGREE II in addition to the 3 domains of AGREE-REX to compare and detect and address any discrepancies in the ratings during the quality assessments of CPGs.
Is the rationale for, and objectives of, the study clearly described?Yes

Are sufficient details of the methods provided to allow replication by others? Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Clinical Practice Guidelines' review, evaluation, adaptation, development, and implementation.Pediatrics and Child healthcare.Healthcare Quality and Safety.Healthcare Informatics.
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Table 4 . Search strategy. Concept Search terms
1: Twin pregnancy "Twin pregnanc*" OR "Multifetal gestation*" OR "Multifetal pregnanc*" OR "Multiple gestation" OR "Multiple pregnanc*" OR "Fraternal twin*" OR "Dichorionic Diamniotic" OR "Dichorionic twin*" OR Dichorionic OR "Dizygotic twin*" OR Dizygotic OR "Nonidentical twin" OR "Non identical twin" AND 2: Clinical guidelines "Antenatal management" OR "Clinical practice guideline*" OR "Clinical Guideline*" OR Guideline* OR Guidance OR "Best practice" OR Standard* OR "Practice guideline*" OR "Practice bulletin*" OR Management OR Managing 1 Clinical Practice Guidelines and Quality Research Unit, Quality Management Department, King Saud University Medical City, Riyadh, Saudi Arabia 2 Pediatrics Department, King Khalid University Hospital, King Saud University Medical City, Riyadh, Saudi Arabia 3 Alexandria Center for Evidence-Based Clinical Practice Guidelines, Alexandria University, 4Guidelines International Network, Perth, Scotland, UK